The long term goal of this project is to develop and commercialize a drug to treat sleep apnea. Sleep apnea is a common medical condition and associated with excessive daytime sleepiness and is a composite risk for cardiovascular morbidity and mortality. Presently, there are no effective pharmacotherapies for individuals with sleep apnea. Growing evidence from both clinical and basic research is quickly approaching the concept that alterations of orexins play a role in the pathology of sleep apnea. Basic research has shown that orexins are directly involved in respiratory control, and a lower level of brain orexins accompanies the frequent appearance of ventilationary pauses. This evidence supports the further study of the direct effects of orexin receptor agonists and antagonists on ventilation;it also suggests that a cell assay should be created to pave the way for the development of a pharmaceutical treatment of sleep apnea. This project will determine the effects of orexin-2 receptor (OX2R) agonists and antagonists on the occurrence of sleep apnea in a mouse model, and it will optimize an established cell-based assay of an OX2R cell line. The hypothesis is that OX2R agonists prevent the occurrence of sleep apnea, and OX2R antagonists produce apnea. The project will measure ventilation rhythm by the plethysmography method combined with sleep recording in the mouse model. Animals will be treated with OX2R agonists or agonists plus antagonists or a control agent, such as artificial corticospinal fluid, via intracerebroventricular injection. A sleep apnea-hypopnea index (AHI) will be calculated for a daily 8 hours of recording data. Comparisons between the baseline and the treatment periods as well as among treatment groups will be evaluated. Optimizing OX2R cell-based assay is the secondary study in this project. Using a cell culture method and a commercially available cell-based assay kit, the project will measure optimal cell response to the OX2R agonist and antagonist treatment. Successful completion of this project will either confirm or refute the hypothesis that OX2R agonists prevent sleep apnea;additionally, it will create a cell line-based assay for the future development of drugs that may eventually lead to effective pharmacotherapy for sleep apnea. PUBLIC HEALTH RELEVANCE: This project will evaluate the potential therapeutic effect of endogenous orexin receptor agonists on sleep apnea in a mouse model and optimize a established cell-based assay for further development in this new direction. Successful completion of this project will establish a strong and solid foundation for the Phase II development of lead compound research in the pharmaceutical treatment of sleep apnea.